The mammalian nuclear pore complex is comprised of∼30 different nucleoporins(Nups).It governs the nuclear import of gene expression modulators and the export of mRNAs.In cardiomyocytes,Na1-H1 exchanger-1(NHE1)is an i...The mammalian nuclear pore complex is comprised of∼30 different nucleoporins(Nups).It governs the nuclear import of gene expression modulators and the export of mRNAs.In cardiomyocytes,Na1-H1 exchanger-1(NHE1)is an integral membrane protein that exclusively regulates intracellular pH(pHi)by exchanging one intracellular H1 for one extracellular Na1.However,the role of Nups in cardiac NHE1 expression remains unknown.We herein report that Nup35 regulates cardiomyocyte NHE1 expression by controlling the nucleo-cytoplasmic trafficking of nhe1 mRNA.The N-terminal domain of Nup35 determines nhe1 mRNA nuclear export by targeting the 5′-UTR(2412 to2213 nt)of nhe1mRNA.Nup35 ablationweakensthe resistance of cardiomyocytes to an acid challenge by depressingNHE1 expression.Moreover,we identify thatNup35 andNHE1 are simultaneously downregulated in ischemic cardiomyocytes both in vivo and in vitro.Enforced expression of Nup35 effectively counteracts the anoxia-induced intracellular acidification.We conclude that Nup35 selectively regulates cardiomyocyte pHi homeostasis by posttranscriptionally controlling NHE1 expression.This finding reveals a novel regulatory mechanism of cardiomyocyte pHi,and may provide insight into the therapeutic strategy for ischemic cardiac diseases.展开更多
基金This work was supported by grants from the National Key Basic Research Program of China(2013CB531100 to Y.-H.C.)the National Natural Science Foundation of China for National Innovative Research Groups(81221001 to Y.-H.C.)+2 种基金the Major International Joint Research Program of China(81120108004 to Y.-H.C.)the Youth Program(81100124 to L.X.)the General Program(81170224 and 81270313 to J.L.and 31271214 to Y.-H.C.)of the National Natural Science Foundation of China.
文摘The mammalian nuclear pore complex is comprised of∼30 different nucleoporins(Nups).It governs the nuclear import of gene expression modulators and the export of mRNAs.In cardiomyocytes,Na1-H1 exchanger-1(NHE1)is an integral membrane protein that exclusively regulates intracellular pH(pHi)by exchanging one intracellular H1 for one extracellular Na1.However,the role of Nups in cardiac NHE1 expression remains unknown.We herein report that Nup35 regulates cardiomyocyte NHE1 expression by controlling the nucleo-cytoplasmic trafficking of nhe1 mRNA.The N-terminal domain of Nup35 determines nhe1 mRNA nuclear export by targeting the 5′-UTR(2412 to2213 nt)of nhe1mRNA.Nup35 ablationweakensthe resistance of cardiomyocytes to an acid challenge by depressingNHE1 expression.Moreover,we identify thatNup35 andNHE1 are simultaneously downregulated in ischemic cardiomyocytes both in vivo and in vitro.Enforced expression of Nup35 effectively counteracts the anoxia-induced intracellular acidification.We conclude that Nup35 selectively regulates cardiomyocyte pHi homeostasis by posttranscriptionally controlling NHE1 expression.This finding reveals a novel regulatory mechanism of cardiomyocyte pHi,and may provide insight into the therapeutic strategy for ischemic cardiac diseases.
